Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of high concentrations of melatonin, and related indole-based and naphthalene-based derivatives, has been examined in the porcine coronary artery, pulmonary artery and the marginal artery of the colon. In addition, we have pharmacologically examined the role of cyclic GMP in the relaxatory action of these agents. Cumulative addition of melatonin (3-300 microM) caused a slowly developing relaxation in all three vascular preparations pre-contracted with 9,11-dideoxy-9a,11a-methanoepoxy prostaglandin F2alpha (U46619), a thromboxane mimetic agent. The estimated pIC50 values were 4.10-3.70 (coronary artery), 3.89 (pulmonary artery) and 3.96 (marginal artery). All melatonin analogues examined also produced concentration-dependent inhibition of U46619-induced contractions of the coronary and marginal arteries in a qualitatively similar manner to melatonin. The rank order of potency (based on the pIC50 values) of these compounds in both vascular tissues was N-[2-(3-ethyl-7-methoxynaphthyl) ethyl]-acetamide (S21634) >2-iodomelatonin = N-[2-(7-methoxynaphth-1-yl)-ethyl]-acetamide (S20098) = N-[2-naphth-1-yl-ethyl]-cyclobutyl carboxamide (S20928) >melatonin >N-acetyl-5-HT. Finally, the pharmacological characteristics of melatonin and S21634 as phosphodiesterase inhibitors were compared to those of zaprinast, a known cyclic GMP-specific phosphodiesterase inhibitor. Zaprinast also caused concentration-dependent inhibition of U46619-induced tone. All three compounds, zaprinast (10 microM), melatonin (300 microM) and S21634 (30 microM), significantly enhanced sodium nitroprusside-induced relaxations. The inhibitory action of zaprinast per se was greater in the presence of the endothelium and significantly attenuated by 3 microM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ), a selective inhibitor of guanylyl cyclase. In marked contrast, the vasorelaxant action of melatonin and S21634 was not affected by the removal of the endothelium or the addition of ODQ. In summary, we have shown that porcine arterial smooth muscle relaxes in response to high concentrations of melatonin and other related melatonin receptor ligands. However, it appears that the receptive site is pharmacologically different from the melatonin receptors currently known and does not involve inhibition of cyclic GMP-specific phosphodiesterase.
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PMID:Pharmacological studies on the inhibitory action of melatonin and putative melatonin analogues on porcine vascular smooth muscle. 1073 Oct 47

The role of heme oxygenase reaction products in modulation of stomach fundus excitability was studied. The presence of constitutive heme oxygenase 2 was verified in myenteric ganglia by immunohistochemistry. The role of inducible heme oxygenase isoenzyme was investigated after invivo treatment of animals with CoCl2 (80 mg kg-1 b.w) injected subcutaneously 24 h before they were killed. This treatment resulted in increased production of bilirubin and positive staining for the inducible isoform in stomach smooth muscle and vast induction in the liver. In both control and treated animals haemin, applied to the bath as a substrate of heme oxygenase caused significant decrease of prostaglandin F2alpha-induced tone, and ameliorated the relaxatory response of the fundic strips to electrical field stimulation. Both effects were antagonized by Sn-protoporphyrin IX, competitive heme oxygenase inhibitor, and were found to be neuronally dependent. In single freshly isolated smooth muscle cells from control animals haemin caused a concentration-dependent increase of the whole cell K+ currents, which was not affected by Sn-protoporphyrin IX, cyclic guanosine monophosphate (cGMP)-dependent protein kinase or guanylyl cyclase antagonists, but was reversed by various antioxidants and abolished by an NO scavenger. In cells from treated animals the K+ current increasing effect of haemin did not depend on the presence of antioxidants, but was abolished by protein kinase G and guanylyl cyclase inhibitors, depletors of intracellular Ca2+ pools or Sn-protoporphyrin IX. Biliverdin did not affect contraction or ionic currents. Thus, this is the first study demonstrating that heme oxygenase is an inducible enzyme in guinea-pigs, which exerts a modulatory role on gastric smooth muscle excitability via carbon monoxide production.
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PMID:Induction of heme oxygenase in guinea-pig stomach: roles in contraction and in single muscle cell ionic currents. 1216 69

The present study investigated the role of ROS (reactive oxygen species) and COX (cyclo-oxygenase) in ethanol-induced contraction and elevation of [Ca2+]i (intracellular [Ca2+]). Vascular reactivity experiments, using standard muscle bath procedures, showed that ethanol (1-800 mmol/l) induced contraction in endothelium-intact (EC50: 306+/-34 mmol/l) and endothelium -denuded (EC50: 180+/-40 mmol/l) rat aortic rings. Endothelial removal enhanced ethanol-induced contraction. Preincubation of intact rings with L-NAME [NG-nitro-L-arginine methyl ester; non-selective NOS (NO synthase) inhibitor, 100 micromol/l], 7-nitroindazole [selective nNOS (neuronal NOS) inhibitor, 100 micromol/l], oxyhaemoglobin (NO scavenger, 10 micromol/l) and ODQ (selective inhibitor of guanylate cyclase enzyme, 1 micromol/l) increased ethanol-induced contraction. Tiron [O2- (superoxide anion) scavenger, 1 mmol/l] and catalase (H2O2 scavenger, 300 units/ml) reduced ethanol-induced contraction to a similar extent in both endothelium-intact and denuded rings. Similarly, indomethacin (non-selective COX inhibitor, 10 micromol/l), SC560 (selective COX-1 inhibitor, 1 micromol/l), AH6809 [PGF2alpha (prostaglandin F2alpha)] receptor antagonist, 10 micromol/l] or SQ29584 [PGH2(prostaglandin H2)/TXA2 (thromboxane A2) receptor antagonist, 3 micromol/l] inhibited ethanol-induced contraction in aortic rings with and without intact endothelium. In cultured aortic VSMCs (vascular smooth muscle cells), ethanol stimulated generation of O2- and H2O2. Ethanol induced a transient increase in [Ca2+]i, which was significantly inhibited in VSMCs pre-exposed to tiron or indomethacin. Our data suggest that ethanol induces vasoconstriction via redox-sensitive and COX-dependent pathways, probably through direct effects on ROS production and Ca2+ signalling. These findings identify putative molecular mechanisms whereby ethanol, at high concentrations, influences vascular reactivity. Whether similar phenomena occur in vivo at lower concentrations of ethanol remains unclear.
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PMID:Ethanol-induced vasoconstriction is mediated via redox-sensitive cyclo-oxygenase-dependent mechanisms. 1995 24


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